Dr Karen Slobod's presentation at Meningitis Research Foundation's 2013 conference, Meningitis & Septicaemia in Children & Adults

1. Development of a Maternal Vaccine for
Group B Streptococcus (GBS)
Karen Slobod MD
5 Nov 2013

2. Agenda
 Epidemiologyand epidemiology
 NVD trivalent maternal vaccine
 Clinical Development Approach
2 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

3. Maternal Immunization: rationale
Prevention of the earliest infections
 H1N11
•
Pregnant women = 13% of all H1N1 deaths
•
Most childhood deaths < 6 mo of age
 Influenza and Tdap routinely recommended in pregnancy2:
 Seasonal influenza vaccination recommended for all pregnant
women
 UK uptake = 40.3%
 Tdap: “Immunisation could be offered at one of the routine
antenatal visits following the routine week 20 anomaly scan”
 UK uptake ≈ 50%
 GBS: Prime candidate for prevention by maternal vaccination
•
95% of all „early‟ infection occurs within 48 hrs, before infant vaccine can
take effect
1 Zuccotti GV, et al. JAMA 304:2360-61
2 JCVI Notes
3 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

4. Group B streptococcus (GBS)
Leading cause of neonatal sepsis and meningitis globally
 Transmission:
• Mother to infant:
20-25% women are colonized (global) ..................................................200/1000
↓
↓
50% of babies born to these mothers are colonized .............................100/1000
↓
↓
2% become infected...............................................................................2/1000
•
•
95% of „early‟ onset disease (EOD: 0-6 days) occurs within 48 hrs
Median age of „late‟ onset disease (LOD: 7-89 days) is 37 days (3rd
quartile is 53 days)
• Maternal vaccination needed to prevent such early infection
4 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

5. GBS Neonatal Disease
Unmet medical need
 Leading cause of neonatal sepsis and meningitis
in the first 3 months of life
 UK incidence: EOD + LOD = 0.7 cases/1000 live
births (~500 cases/yr)1
 Case fatality rate (UK): 8-9%2-3
1
Lamagni TL, et al. CID 57:682; 2013.
K, et al. Lancet 2011
3 Weisner 2004; Clin Infect Dis 2004; 38: 1203-08
2 Edmond
5 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

6. GBS: Important cause of bacterial meningitis
Unmet medical need
 Meningitis occurs among 7% of EOD and 27%
LOD1
 Case fatality rate among meningitis cases: up to
23% in preterm infants and 12% in term infants2.
 Long-term neurologic sequelae/disability in
almost half of GBS meningitis cases3,4
1
Phares CR, et al. JAMA 2008..
2007 Health Technologies Assess (11) No 29; 2007
3 Libster R, et al. Pediatrics, 2012.
4 NEJM 357:918-25, 2007
2 Colbourn
6 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

7. Prevention: No vaccine yet licensed
Intrapartum antibiotic prophylaxis (IAP) only prevention
 IAP = Intravenous ampicillin q4h during labor for
women at risk. Risk determined:
• Universal screening: All pregnant women are screened at ~35-37
wks gestation → all colonized women receive IAP (e.g. USA)
• Clinical factors: previous infant with GBS disease, prematurity,
PROM, fever (e.g. UK)
7 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

8. GBS: Universal screening and IAP (US)
Reduced but not eradicated disease
Incidence of invasive GBS disease among infants (recommendations
issued 1993)
Cases / 1,000 live births
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
8 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

9. GBS: Risk-based IAP (UK)
Little change with risk-based IAP
In the UK, IAP-eligible women are identified via risk factors; no evident decrease in cases since the
recommendations were issued in 2003
Incidence of EOD and LOD in the England and Wales and N. Ireland between 2003-2011
RCOG guidelines for GBS implemented
Source: Lamagni, T et al. CID, 2013
9 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

10. GBS: Lead cause pediatric bacterial meningitis (US)
Causes >85% meningitis in infants <2mo (US)
1.
Thigpen MC, et al. Bacterial meningitis in the United States 1998-2007. NEJM 364:2016, 2011.
10 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

11. GBS: Maternal vaccine can be protective
Long-standing data supports protection of maternal anti-CPS Ab
Ab against CPS protects against neonatal infection:
1. GBS capsular polysaccharide conjugate (CPS-CRM197) vaccines
protect in GBS neonatal pup challenge model1
2. Passive transfer of anti-CPS Ab protects newborn mice2
3. Low levels of maternal anti-CPS Ab correlate with neonatal disease
susceptibility3
4. Higher levels of maternal anti-CPS Ab correlate with reduced risk of
neonatal disease4,5
1Vaccine
2001;19:2118-2126
1992;166:635-639
3NEJM 1976; 294:753-756
4JID 2001;184:1022-1028
5JID11 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
2004;190:928-934
2JID

12. Key data: GBS CPS-specific Ab protects
Pups born to vaccinated dams survive lethal challenge
Measure
2 day survival
+
Females immunized
Mating
(0 and 21 days)
(day 21)
GBS challenge of pups
at 24-48 hrs age
(intraperitoneal, 90% LD)
Vaccine
serotype Challenge strain (type)
Ia
090 (Ia)
Ib
7357B (Ib)
III
COH1 (III)
% Survival (Alive/Treated)
CRM-conjugate
PBS
86% (54/63)
0% (0/59)
73% (71/97)
0% (0/38)
93% (95/102)
2% (1/48)
Anti-CPS Ab protects - NVD glycoconjugates protect.
12 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

13. Novartis GBS vaccine
Trivalent glycoconjugate vaccine
 Vaccine: CRM197 conjugated capsular polysaccharide representing
three serotypes (at 1:1:1 ratio):
»Ia
»Ib
»III
Bacterial capsular
polysaccharide
CRM protein
 Trivalent coverage ≈ 79% globally
13 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
Glycoprotein
conjugate

14. GBS: Maternal vaccination allows infant protection
Placental transfer increases markedly >32 wks
Decay of passively
Passive Ab transfer occurs largely in third trimester
% maternal Ab in cord blood
transferred Ab
120
100
80
60
40
20
3-6 mo
0
0
20
Gestational Age
14 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
28
32
40

15. Novartis: GBS vaccine development
Monovalent:
Phase I
Trivalent: Phase I
Serotype Ia
Serotype Ib & III)
Trivalent (Ia, Ib & III), NPG
Phase Ib/II
Trivalent PG
Phase II
Trivalent HIV+/- PG
Trivalent PG (functional Ab)
Trivalent PG US
Formulation
15 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
NPG: Non-pregnant
PG: Pregnant
Trial complete
Recruiting complete
FSFV in next 9 mo

16. Study 1: GBS Trivalent Vaccine in Non-pregnant women
No added benefit from aluminum hydroxide, 2 injections or 20 vs 5 ug
Adjuvant
No Alum
Injection #
1
Placebo
(saline)
2
Alum
2
1
2
Dose (each GC)
5 µg
20 µg
5 µg
20 µg
5 µg
20 µg
5 µg
20 µg
0 µg
n
40
38
40
40
40
39
40
38
18
Cumulative Percentage
Reverse Cumulative Ab Distribution: Serotype Ia at day 61
GBS ELISA Concentrations ( g/mL)
16 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential

17. Study 2: Phase Ib/II study in pregnant women
Objective: Select dosage in pregnant women
 Subjects: Healthy, pregnant women between 28-35 wks gestation (18-40 yrs)
 Study site: South Africa
GBS
Vx dosage1
(Ia/Ib/III GC)
Study subjects (n)
Delivery
0.5/0.5/0.5 µg
80
2.5/2.5/2.5 µg
80
5/5/5 µg
80
Placebo (saline)
80
1 Formulated without adjuvant; administered as a single injection
17 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential

18. Study 2: Ph II Dose-ranging in pregnant women
All subjects
Reverse Cumulative Distribution at delivery: Serotype Ia
GBS Ia ELISA Delivery
5 g
Cumulative Percentage
2.5 g
0.5 g
Placebo
GBS ELISA Concentrations ( g/mL)
18 | ESPID | Karen Slobod | 30 May 2013 | GBS Vaccine | Confidential
- _____ (N = 75)
*-
--------- (N = 77)
- ______ (N = 77)
- _ _ _ _ (N = 76)

19. Ph II Dose-ranging in PG: Serotype Ia
Subjects < limit of detection at baseline
GBS Ia ELISA
Reverse Cumulative Distribution at delivery: Serotype Ia
Delivery
5 g
Cumulative Percentage
2.5 g
0.5 g
Placebo
 5 ug dosage superior
GBS ELISA Concentrations ( g/mL)
19 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
- _____ (N = 43)
*-
--------- (N = 42)
- ______ (N = 31)
- _ _ _ _ (N = 39)

20. Novartis GBS Vaccine
Immunogenic and well-tolerated in NPG and PG women
 5/5/5 µg
 Single injection administered between 28-35 weeks
gestation
 No adjuvant (no preservatives)
20 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

21. GBS Maternal Vaccine: Phase III Study
Enroll and vaccinate mothers; follow mothers and infants
 Phase III study:
• Size: >10,000 mothers → >10,000 infants
Infant
Enroll
Mothers
(>10,000)
Immunize
Delivery
Mother
(>10,000)
• Eligibility: women between 28-35 wks gestation
• End-points: Mother/infant safety; vaccine immunogenictiy (efficacy);
infant response to CRM-containing vaccines
21 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

22. GBS Maternal Vaccine Development
Next Steps
 Complete Ph II dose-ranging studies
- placental transfer
- functional Ab
 Ph III maternal/infant study start
• Planned start Q1 2015
• Global study enrolling >10k pregnant women in EU/US/global
 Ongoing advocacy for role of maternal vaccination in
prevention of neonatal disease
22 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only

23. Contributors
GBS Global Program
Team
Stephen Cho
Brian Cooper
Marianne Cunnington
Laura Deschenes
Peter Dull
Guido Grandi
Dominika Kovacs
Martha Leibbrandt
Imma Margarit Y Ros
Mariska Mulder
Research
Fabiana Baldoni
Friedhelm Helling
Gabriella Rolli
Mario Contorni
Lorenzo Tarli
Concetta Cicala
Massimo Pacini
Hans Joachim Mai
Manfred Boese
Melanie Muche
Francesca Titta
Francesco Norelli
Frederica Sponga
Valeria Carinci
John Telford
Paolo Costantino
Domenico Maione
Francesco Berti
Emanuela Palla
Elena Mori
Barbara Baudner
Mikkel Nissum
Maria Rosaria Romano
Marzia Giuliani
TechOps/TD
Stefano Ricci
Stefania Berti
Stefania Ferrari
Stefania Pezzotti
Antonella Damarini
23 | MRF | K Slobod | 5 Nov 2013 | Maternal GBS Vx | Business Use Only
Development
•
•
•
•
•
•
•
Pietro Forte
Irving Boudville
Richard de Rooij
Geert Prins
Anke Hilbert
Annette Karsten
Rachid Marhaba
Silvia Benocci
Sue Fekete
Lisa Bedell
Allen Izu
Katherine Lanier
Wayne Woo
Alessandra Schiavone
Jonathan Go
Narcisa Cuceanu
Ana Vila Real
Aldo Schepers
Renate Enzinga